Rett Syndrome (RS) may involve a genetic defect in development of specific groups of neurons in the immature brain. This project will extend studies of the abnormal neurotransmitter circuitry in RS by examining postmortem brain tissue using neurotransmitter receptor autoradiography and by assessing the effects of neuronal degeneration in a rodent model. Following up on neurochemical observations made by Dr. Wenk in the previous grant period (Project 3a), postmortem RS brain, along with age- and sex-matched control brain will be prepared to visualize binding sites for excitatory amino acid receptor subtypes and messenger RNA for these receptors, D1 and D2 dopamine receptors, dopamine reuptake sites, muscarinic receptors and nicotinic receptors. These autoradiographic studies will allow us to assess abnormalities in both the quantity and distribution of receptors for specific groups of neurons that may participate in the neurodegenerative stage of RS. Experiments utilizing a model of neuronal degeneration in dopaminergic and cholinergic projections from the brainstem and diencephalon to the basal ganglia and cerebral cortex in neonatal mice will allow us to interpret the results of analyzing the human tissue. The animal model will also provide information about the effects of injury to these projections on neurons in their terminal fields. Potential therapeutic interventions including supplementation with the growth factors, nerve growth factor (NGF), and brain derived neurotrophic factor (BDNF) will also be tested in the rodent model. The model will also be useful for understanding molecular mechanisms involved in neuronal degeneration and regeneration that may be disrupted in RS.